DESCRIPTION (taken directly from the application) There are several requirements which must be met before replication deficient adenovirus can be considered a viable vehicle for the delivery of genes into the brain parenchyma for correction of inherited disorders of metabolism. First, the adenovirus must be capable of infecting multiple cell types relatively efficiently. Second, transgene expression must occur in the infected cells and it must persist a reasonable period of time. Third, the adenovirus must be capable of infecting a large proportion of the brain for generalized correction. Because our laboratory and others have already demonstrated the ability of adenovirus to satisfy the first requirement, it is the purpose of this proposal to develop methods which will satisfy the latter two; namely, the problems associated with persistence and delivery. We hypothesize that i) persistence of adenoviral gene expression can be improved by altering the production of endogenous viral proteins through vector sequence manipulation and/or administration of exogenous immunosuppressive cytokines at the time of adenoviral infections, and ii) delivery techniques can be developed that permit infection of a large portion of the CNS either through blood-brain barrier disruption or improved intraventricular and parenchymal delivery schemes. Although the long term goal of these studies is aimed at the treatment of neurologic manifestations of inherited disease, these vectors should be generally useful in transferring genes to other affected tissues. In addition, the techniques that will be developed for global delivery of adenovirus in the CNS should be applicable to other vectors.